Primary cultures of bone marrow stromal cells (MSCs) contain pluripotent cells with a robust ex vivo expansion capacity (Pittenger et al. Science. 1999 Apr. 2; 284 (5411):143-7; Deans et al. Exp Hematol. 2000 August; 28(8):875-84). Pre-clinical and clinical studies have demonstrated that MSCs can be used for tissue repair (Yoon et al. Clin Invest. 2005 February; 115 (2):326-38; Pittenger et al. Circ Res. 2004 Jul. 9; 95(1):9-20), for in trans delivery of therapeutic gene products (Horwitz et al. Proc Natl Acad Sci USA. 2002 Jun. 25; 99(13):8932-7; Wang et al. Proc Natl Acad Sci USA. 2005 Jan. 4; 102(1):186-91; Batholomew et al. Hum Gene Ther. 2001 Aug. 10; 12(12):1527-41; Chuah et al. Hum Gene Ther. 2000 Mar. 20; 11 (5):729-38; Studeny et al. Cancer Res. 2002 Jul. 1; 62(13):3603-8; Eliopoulos et al. Mol Ther. 2004 October; 10(4):741-8; Stagg et al. Hum Gene Ther. 2004 June; 15(6):597-608) and for enhancing allogeneic hematopoietic stem cell engraftment (Koc et al. Bone Marrow Transplant. 2002 August; 30(4):215-22). Under specific culture conditions, MSCs can differentiate along multiple cell lineages, including adipocytes, chondrocytes, osteocytes, myocytes, astrocytes, neurons, endothelial cells and lung epithelial cells (Pittenger et al. Science. 1999 Apr. 2; 284 (5411):143-7; Wakitani et al. Muscle Nerve. 1995 December; 18(12):1417-26; Woodbury et al. J Neurosci Res. 2000 Aug. 15; 61(4):364-70; Reyes et al. Blood. 2001 Nov. 1; 98(9):2615-25; Wang et al. Proc Natl Acad Sci USA. 2005 Jan. 4; 102(1):186-91). Since no single surface marker has been described for purification, MSCs are generally isolated based on their adherence to tissue culture plates, resulting in a semi-homogenous population characterized by the absence of hematopoietic and endothelial surface markers such as CD45 and CD31, and by the expression of CD105, CD73 and CD44 (Pittenger et al. Circ Res. 2004 Jul. 9; 95(1):9-20). MSCs express low levels of major histocompatibility complex (MHC) class I molecules while, as a general rule, they do not constitutively express MHC class II molecules (LeBlanc et al. Exp Hematol. 2003 October; 31(10):890-6; Tse et al. Transplantation. 2003 Feb. 15; 75(3):389-97; DiNicola et al. Blood. 2002 May 15; 99(10):3838-43). One study, however, reported constitutive MHC class II expression on MSCs (Potian et al. J Immunol. 2003 Oct. 1; 171 (7):3426-34). Both MHC class I and class II molecules get upregulated following IFNγ treatment, with a more heterogeneous expression between individual cells for MHC class II molecules (Gotherstrom et al. Am J Obstet Gynecol. 2004 January; 190 (1):23945; LeBlanc et al. Exp Hematol. 2003 October; 31(10):890-6; Krampera et al. Blood. 2003 May 1; 101(9):3722-9). Costimulatory molecules such as CD80, CD86, CD40 and CD40L are not known to be expressed nor induced on human MSCs, while mouse MSCs can be found to express CD80 (Krampera et al. Blood. 2003 May 1; 101 (9):3722-9).
MSCs are known to secrete a wide spectrum of growth factors and cytokines implicated in different aspects of hematopoiesis (Deans et al. Exp Hematol. 2000 August; 28(8):875-84). MSCs therefore possess properties of their own that may influence, positively or negatively, the desired therapeutic effect. One important feature of MSCs is their recently identified immunosuppressive properties against allogeneic immune responses. It has been shown that MSCs are able: (1) to suppress the proliferation of allogeneic T cells in response to mitogen or allogeneic cells (DiNicola et al. Blood. 2002 May 15; 99(10):3838-43; Djouad et al. Blood. 2003 Nov. 15; 102(10):3837-44; Krampera et al. Blood. 2003 May 1; 101(9):3722-9; Tse et al. Transplantation. 2003 Feb. 15; 75(3):389-97; LeBlanc et al. Exp Hematol. 2003 October; 31(10):890-6); (2) to inhibit the production of IFNγ and tumor-necrosis factor (TNF)-α and increase the production of IL-10 (Aggarwal et al. Blood. 2005 Feb. 15; 105(4):1815-22); (3) to induce T cell division arrest anergy (Glennie et al. Blood. 2005 Apr. 1; 105(7):2821-7); (4) to inhibit the maturation and function of antigen presenting cells such as monocytes and dendritic cells (Beyth et al. Blood. 2005 Mar. 1; 105(5):2214-9; Jiang et al. Blood. 2005 May 15; 105(10):4120-6); (5) to decrease alloantigen-specific cytotoxicity of CD8 T cells and natural killer (NK) cells; and (6) to favor the differentiation of CD4 T cells with presumed regulatory activity (Maccario et al. Haematologica. 2005 April; 90(4):516-25). The clinical potential of the immunosuppressive properties of MSCs has been exemplified by LeBlanc and colleagues (Lancet. 2004 May 1; 363 (9419):1439-41) who reported in a case study that administration of haploidentical human MSCs following allogeneic stem cell transplantation could reverse the severe grade IV acute graft-versus-host disease (GVHD) of a patient. At present, the exact mechanism responsible for MSCs-mediated immunosuppression remains imprecise. Soluble factors such as hepatocyte growth factor (HGF), transforming growth factor (TGF)-β1 (DiNicola et al. Blood. 2002 May 15; 99(10):3838-43), indoleamine 2,3-dioxygenase (IDO) (Meisel et al. Blood. 2004 Jun. 15; 103(12):4619-21), IL-10 (Beyth et al. Blood. 2005 Mar. 1; 105(5):2214-9) and unidentified factors (Tse et al. Transplantation. 2003 Feb. 15; 75(3):389-97, Djouad et al. Blood. 2003 Nov. 15; 102(10):3837-44; Le Blanc et al. Scand J Immunol. 2004 September; 60(3):307-15), as well as contact-dependent mechanisms (Beyth et al. Blood. 2005 Mar. 1; 105(5):2214-9; Krampera et al. Blood. 2003 May 1; 101(9):3722-9) have been implicated.
If the immunosuppressive effects of MSCs on allogeneic immune responses have been well described, the effect of MSCs on syngeneic immune responses has been largely overlooked.
A better understanding of the syngeneic immune response is desirable to exploit the immunogenic properties of MSCs.